Wnt proteins constitute a large family of secreted glycoproteins that activate signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity. Wnt proteins are capable of signaling through several pathways, the best-characterized being the canonical pathway through β-catenin (Wnt/β-catenin signaling). Deregulation of Wnt/β-catenin signaling is frequently found in many human cancers like colorectal cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, and many others.
TNIK is known as one of STE20 family kinases that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. Recently, TNIK was identified as one of 70 proteins immunoprecipitated commonly with anti-TCF4 (T-cell factor-4) and anti-β-catenin antibodies in two colorectal cancer cell lines DLD1 and HCT-116 (Shitashige M, et al., Gastroenterology 2008, 134:1961-71). Recent studies has been shown that TNIK plays critical roles in canonical Wnt signaling pathway, and therefore TNIK can be a promising target to ablate aberrant Wnt signaling in tumors (Shitashige M, et al., Cancer Res; 70(12); 5024-33 (2010)). Namely, small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice.
Evaluation methods for utility of the present invention which is the screening of an anti-cancer agent have already been described in WO 2009/104413 filed by the present inventors. WO 2010/64111 filed by the present inventors discloses novel aminothiazole derivatives as potent TNIK inhibitors and the effects of TNIK inhibitors on the transcriptional activity of the β-catenin and TCF4 complex. However, it has not been disclosed that thiazole compounds having bicyclic structures of the present invention are useful as TNIK inhibitors until now.